Ammonul

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Ammonul

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Management of Acute Hyperammonemia

Any episode of acute symptomatic hyperammonemia should be treated as a life-threatening
emergency. Uncontrolled hyperammonemia can rapidly result in brain damage or
death, and prompt use of all therapies necessary, including hemodialysis, to
reduce ammonia levels is essential.

Hyperammonemic coma (regardless of cause) in the newborn infant should be aggressively
treated while the specific diagnosis is pursued.

Hemodialysis should be promptly initiated in all newborn patients. A blood
flow rate of 150 mL/min/m² should be targeted (ammonia clearance [mL/min]
is similar to the blood flow rate [mL/min] through the dialyzer). Clearance
of ammonia is approximately ten times greater by hemodialysis than by peritoneal dialysis or hemofiltration. Exchange transfusion is ineffective in the management
of hyperammonemia. Hemodialysis may be repeated until the plasma ammonia level
is stable at normal or near normal levels.

Hyperammonemia due to urea cycle disorders should be managed in coordination
with medical personnel experienced in metabolic disorders. Ongoing monitoring
of plasma ammonia levels, neurological status, laboratory tests, and clinical
response in patients receiving AMMONUL is crucial to assess patient response
to treatment.

Decreased Potassium Levels

Because urine potassium loss is enhanced by the excretion of the nonreabsorbable
anions, phenylacetylglutamine and hippurate, plasma potassium levels should
be carefully monitored and appropriate treatment given when necessary.

Conditions Associated with Fluid Overload

AMMONUL contains 30.5 mg of sodium per mL of undiluted product. Thus, AMMONUL
should be used with great care, if at all, in patients with congestive heart
failure or severe renal insufficiency, and in clinical states in which there
is sodium retention with edema. Discontinue administration of AMMONUL, evaluate
the patient, and institute appropriate therapeutic countermeasures if an adverse
event occurs.

Extravasation

Administration must be through a central line. Administration through a peripheral
line may cause burns. Bolus infusion flow rates are relatively high, especially
for infants [see DOSAGE AND ADMINISTRATION]. Extravasation of AMMONUL
into the perivenous tissues may lead to skin necrosis. If extravasation is suspected,
discontinue the infusion and resume at a different infusion site, if necessary.
The infusion site must be monitored closely for possible infiltration during
drug administration. Do not administer undiluted product.

Neurotoxicity of Phenylacetate

Because of prolonged plasma levels achieved by phenylacetate in pharmacokinetic
studies, repeat loading doses of AMMONUL should not be administered. Additionally,
neurotoxicity was reported in cancer patients receiving intravenous phenylacetate,
250–300 mg/kg/day for 14 days, repeated at 4-week intervals. Manifestations
were predominantly somnolence, fatigue, and lightheadedness, with less frequent
headaches, dysgeusia, hypoacusis, disorientation, impaired memory, and exacerbation
of a preexisting neuropathy. The acute onset of symptoms upon initiation of
treatment and reversibility of symptoms when the phenylacetate was discontinued
suggest a drug effect. [See Animal Toxicology and/or Pharmacology]

Hyperventilation and Metabolic Acidosis

Due to structural similarities between phenylacetate and benzoate to salicylate,
AMMONUL may cause side effects typically associated with salicylate overdose,
such as hyperventilation and metabolic acidosis. Monitoring of blood chemistry
profiles, blood pH and should be performed.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals have not been performed to evaluate the carcinogenic
potential of AMMONUL. Studies to evaluate the possible impairment of fertility
or mutagenic potential of AMMONUL have not been performed. Results indicate
that sodium benzoate is not mutagenic or carcinogenic, and does not impair fertility.

Use In Specific Populations

Pregnancy

Pregnancy Category C. Animal reproduction studies have not been conducted with
AMMONUL. It is not known whether AMMONUL can cause fetal harm when administered
to a pregnant woman or can affect reproduction capacity. Thus, AMMONUL should
be given to a pregnant woman only if clearly needed.

Nursing Mothers

It is not known whether sodium phenylacetate, sodium benzoate, or their conjugation
products are excreted in human milk. Because many drugs are excreted in human
milk, caution should be exercised when AMMONUL is administered to a nursing
woman.

Pediatric Use

AMMONUL has been used as a treatment for acute hyperammonemia in pediatric
patients including patients in the early neonatal period [see DOSAGE AND
ADMINISTRATION].

Geriatric Use

Clinical studies of AMMONUL did not include any patients aged 65 and over to
determine whether they respond differently from younger patients. Urea cycle
disorders are presently diseases of the pediatric and younger adult populations.
No pharmacokinetic studies of AMMONUL have been performed in geriatric patients.
In general, dose selection for an elderly patient should be cautious, usually
starting at the low end of the dosing range, reflecting the greater frequency
of decreased hepatic, renal, or cardiac function, and concomitant disease or
other drug therapy in this patient population.

Gender

Pharmacokinetic parameters of AMMONUL were compared in healthy males and females.
Bioavailability of both benzoate and phenylacetate was slightly higher in females
than in males. However, conclusions cannot be drawn due to the limited number
of subjects in this study.

Hepatic Insufficiency

Limited information is available on the metabolism and excretion of sodium
phenylacetate and sodium benzoate in patients with impaired hepatic function.
However, metabolic conjugation of sodium phenylacetate and sodium benzoate is
known to take place in the liver and kidney. Therefore, caution should be used
in administering AMMONUL to patients with hepatic insufficiency.

Renal Impairment

The drug metabolites of AMMONUL (phenylacetylglutamine and hippurate) and subsequently
ammonia are primarily excreted by the kidney. Therefore, use caution and closely
monitor patients with impaired renal function who receive AMMONUL.

Last reviewed on RxList: 7/27/2011
This monograph has been modified to include the generic and brand name in many instances.